Interferon-elicited lipoprotein metabolism in lung fibroblasts facilitates premetastatic niche formation

While premetastatic niche formation is known to affect primary tumors lung metastases, the role of lung stromal cells in this process remains unclear. Here, by performing multiomics sequencing, we identify interferon-regulated CD34+fibroblasts that reshape the immunosuppressive lung microenvironment via VLDLR-mediated lipoprotein metabolism activation. Increased lipoprotein uptake facilitates intracellular lipid accumulation, followed by CD155 expression in fibroblasts. CD155+fibroblasts strongly induce cytotoxic CD8+T and NK cell exhaustion, resulting in the formation of a premetastatic niche. The genetic disruption of the interferon–VLDLR–CD155 axis robustly reinstates immune surveillance and suppresses lung metastasis in multiple tumor models. Notably, interferon-based therapy is potentiated by specific silencing of the interferon response in fibroblasts or CD155 blockade. Moreover, the FTO-YTHDF2-mediated STAT1 m6A modification results in differences in the interferon response. Collectively, our findings reveal how interferon-induced metabolic rewiring in fibroblasts promotes metastatic competence via CD155-mediated immune evasion, suggesting stromal-targeted strategies for treating lung metastasis. The formation of pre-metastatic niches can be driven by local stromal signals. Here, the authors discover that lung CD34+fibroblasts promote the formation of a premetastatic niche via an upregulation of IFN-I response-governed CD155 expression that drives cytotoxic NK and T-cell exhaustion.